This study is in response to the mission of the National Institute of Biomedical Imaging and Bioengineering (Research and development of nano-scale technologies for biomedical imaging) and the National Cancer Institute (cancer theranostics with improved targeting, biocompatibility and imaging contrast capability). A major issue with current cancer therapy is the prevalence of undesired dose-limiting activity upon non-cancerous tissues and organs. This is further compounded by limited ability in monitoring drug delivery, pharmacodynamics and therapeutic response in vivo. To address the urgent need for novel approaches to selectively targeting therapeutics to tumor, we propose to develop and test new, activatable, theranostic (combined therapeutic and diagnostic) nanoparticles that release the potent therapeutic drug azademethylcolchicine after cleavage by specific tumor enzymes (matrix metalloproteinases, MMP-14), thereby leading to selective toxic effects in MMP-14 expressing tumors, but not visceral organs. In addition, the iron oxide core of the nanoparticles can be detected with MR imaging, thereby enabling in vivo drug tracking. Thus, the major goal of our project is to develop novel tumor-enzyme activatable theranostic nanoparticles (TNPs), which exert selective toxic effects in MMP-14 expressing tumors, but not normal organs, and which enable real-time monitoring of drug accumulation and localization at tumors with Magnetic Resonance (MR) imaging. Realizing this goal will lead to substantially improved efficacy of cancer therapies, and allow guiding personalized therapy regimens via direct in vivo drug tracking and therapeutic response monitoring with MR imaging. The approach relies on the high prevalence of MMP-14 in a large variety of breast cancers and other cancers, a proven MMP-14 activatable prodrug strategy, and a nanocarrier platform based on FDA-approved superparamagnetic iron oxide nanoparticles. We hypothesize that our TNPs will be converted from a non-toxic to an active therapeutic agent within MMP-14 expressing tumors, releasing the potent therapeutic drug azademethylcolchicine, and inducing a significant antitumor effect, whilst avoiding toxic side effects to normal tissues. In addition, we postulate that the iron oxide nanoparticle moiety will allow real-time monitoring of drug accumulation and localization at tumors with MR imaging. If successful, the proposed novel, multifunctional TNPs hold the potential to substantially improving therapeutic efficacy and monitoring whilst simultaneously reducing dose-limiting toxicities, thereby increasing the therapeutic index. Our investigations could be in principle readily translated to clinical applications, may directly impact clinical decision-making, and ultimately, help to improve and tailor individualized therapeutic options. The proposed concept would have broad applications and could be extended to a variety of other cancer types.